Thermal detection of vulnerable plaque

doi:10.1016/S0002-9149(02)02962-4

The American Journal of Cardiology

Volume 90, Issue 10, Supplement 3, 21 November 2002, Pages L36-L39

https://doi.org/10.1016/S0002-9149(02)02962-4 Get rights and content

Abstract

In 1996, we showed that inflamed atherosclerotic plaques give off more heat and that vulnerable plaques may be detected by measuring their temperature. Plaque temperature is correlated directly with inflammatory cell density and inversely with the distance of the cell clusters from the luminal surface. It is inversely related to the density of the smooth muscle cells. We found no significant association between temperature heterogeneity and presence of Chlamydia pneumoniae in plaque or the gross color of human atherosclerotic carotid plaques. We also found pH heterogeneity in plaques from human carotid artery and aortas of Watanabe atherosclerotic rabbits and apolipoprotein E–deficient mice. Areas with lower pH had higher temperature, and areas with a large lipid core showed lower pH with higher temperature, whereas calcified regions had lower temperature and higher pH. We also developed a thermography basket catheter and showed in vivo temperature heterogeneity in atherosclerotic lesions of atherosclerotic dogs and Watanabe rabbits. Thermal heterogeneity was later documented in human atherosclerotic coronary arteries. Temperature difference between atherosclerotic plaque and healthy vessel wall is related to clinical instability. It is correlated with systemic markers of inflammation and is a strong predictor of adverse cardiac events after percutaneous interventions. Thermography is the first in a series of novel “functional” imaging methods and is moving to clinical trials. It may be useful for a variety of clinical and research purposes, such as detection of vulnerable plaques and risk stratification of vulnerable patients.

Section snippets

Mechanism of heat production in atherosclerotic plaques

Macrophages are metabolically active cells with a very high turnover rate of adenosine triphosphate.3 In addition to oxidative reactions in the cytosol, they strongly express mitochondrial uncoupling protein (UCP)-2 and UCP-3. UCPs are homologues of thermogenin (UCP-1), which is responsible for thermogenesis in brown fat tissue.4 High metabolic rate and consumption of glucose and oxygen may lead not only to increase in plaque temperature but also accumulation of lactate, due to anaerobic

Ex vivo thermal detection studies

In 1996, for the first time, we showed that there is marked temperature heterogeneity over plaque surface and that “hot plaques” are inflamed. We measured the intimal surface temperatures at 20 sites of 50 samples of carotid artery taken at endarterectomy from 48 patients.5 Surface temperature of plaques at different points showed marked and reproducible heterogeneity (with temperature differences of 0.2 to 2.2° C). Temperature correlated positively with cell density and inversely with the

In vivo thermal detection: animal studies

In vivo, we used a thermistor and found a thermal heterogeneity of 1.5 to 2.0° C inside the intact aorta of the Watanabe hypercholesterolemic rabbits. Using an infrared camera, we could also demonstrate thermal heterogeneity on the exterior of the aorta of the Watanabe rabbits (in the presence of normal blood flow). We also used the infrared camera for thermal imaging of the beating heart in a canine model of atherosclerosis and could image the blood flow and the nonuniform and heterogeneous

In vivo thermal detection: human studies

In our preliminary studies, we found considerable in vivo thermal heterogeneity in humans by using infrared thermography during operation on atherosclerotic patients. In most cases, the indication for surgery was carotid stenosis and a transient ischemic attack or stroke. In 8 different procedures, including carotid endarterectomy, aortofemoral bypass, and femoropopliteal bypass, we demonstrated significant in vivo thermal heterogeneity even in the presence of blood flow.

To date, the US Food

Conclusion

Thermography is moving to clinical trials. It is the first in a series of novel functional imaging methods that provide information about the metabolic activity of atherosclerotic plaques. If proved to be safe and reproducible, it may be used in detection of vulnerable plaques, risk stratification of vulnerable patients, and can be used by both the researchers and clinicians for a variety of purposes. Simplicity of design and application make thermography a good candidate for combination with

References (17)

P.K. Shah
Pathophysiology of plaque rupture and the concept of plaque stabilization
Cardiol Clin
(1996)
C. Stefanadis et al.
Heat production of atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes
J Mol Cell Cardiol
(2000)
C. Stefanadis et al.
Increased local temperature in human coronary atherosclerotic plaquesan independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention
J Am Coll Cardiol
(2001)
R. Ross
Atherosclerosis—an inflammatory disease
N Engl J Med
(1999)
P. Newsholme et al.
Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture
Biochem J
(1989)
M.K. Kockx et al.
Expression of the uncoupling protein UCP-2 in macrophages of unstable human atherosclerotic plaques
Circulation
(2000)
W. Casscells et al.
Thermal detection of cellular infiltrates in living atherosclerotic plaquespossible implications for plaque rupture and thrombosis
Lancet
(1996)
N. Naghavi et al.
pH heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque
Atherosclerosis
(2002)

There are more references available in the full text version of this article.

Cited by (62)

Aptamer and PNIPAAm co-conjugated nanoparticles regulate activity of enzyme with different temperature
2016, Talanta
Citation Excerpt :
The optimum reaction temperature of enzymes in human body is 37 °C, which mean if reaction temperature is higher or lower than 37 °C, activity of enzyme will be reduced. Thrombin is a key enzyme in coagulation cascade, and the temperature near plaques is higher than the normal body temperature [30,31]. Here, we developed this inhibitor that was able to reduce the activity of thrombin at 37 °C, while increase its activity at 25 °C, which was different to the normal.
In this paper, we described a temperature responsive nano-system that can regulate activity of enzyme with different temperature. Temperature responsive polymer poly(N-isopropylacrylamide) (PNIPAAm), with low critical solution temperature of 32 °C, was synthesized with thiol modification. PNIPAAm and thrombin aptamer were co-functionalized on the surface of gold nanoparticles for effective regulation of thrombin activity with different temperature. On the one hand, we studied the thermal responsive properties of this inhibitor via UV–visible spectroscopy. On the other hand, we investigated the regulation of thrombin activity by this platform with different temperature. The PNIPAAm chains could extend and shrink with different temperature, which suggested that PNIPAAm on the surface of gold nanoparticles could regulate interaction between thrombin and aptamer according to temperature changing. At 25 °C, PNIPAAm was hydrophilic extended state, which blocked the interaction between thrombin and aptamer on the surface of gold nanoparticles, therefore thrombin activity had no change. On the contrary, at 37 °C, PNIPAAm transformed from hydrophilic extended state to hydrophobic shrank state, allowing the aptamer to capture thrombin, inhibiting the activity of thrombin. More interestingly, this regulation was reverse to normal condition, where 37 °C was always the optimum reaction temperature for most of human enzymes. This system we prepared was opposite, which was capable of inhibiting the thrombin activity at 37 °C. Furthermore, this was the first report of regulation of thrombin activity using this temperature responsive platform.
Effect of magnetic field on temperature distribution of atherosclerotic plaques in coronary artery under pulsatile blood flow condition
2013, International Journal of Thermal Sciences
Temperature heterogeneity in plaque containing inflammatory cells can cause thermal stress, and speeds up plaque growth or rupture process. Activated inflammatory cells embedded in plaques release heat while the plaque is cooled by blood flow. In the present work, arterial wall temperature distribution of atherosclerotic Right Coronary in the presence of external uniform and multi-directional magnetic field is investigated by numerical methods. The magnetic field is applied in both x and y directions. An advanced coupled FEM–FVM algorithm is used to determine temperature distribution inside the artery. Transient Navier–Stokes and energy equations in 2D idealized arterial model of a bending artery coupled with Maxwell's equations are discretized using the Finite-Volume Method and solved by SIMPLE algorithm in curvilinear coordinate to analyze pulsatile blood flow, whereas the transient heat conduction equation in the plaque is solved simultaneously with these equations using Finite-Element Method. The plaque temperature, Nusselt Number and heat flux at the plaque/lumen interface is obtained for various moments of cardiac cycle and different states of magnetic field to investigate influence of produced electromagnetic force on the cooling effect of blood. It is observed that how magnetic field modifies the temperature heterogeneity of plaque and decreases probability of rupture of Atherosclerotic plaque.
Three complementary techniques for the clarification of temperature effect on low-density lipoprotein-chondroitin-6-sulfate interaction
2013, Analytical Biochemistry
Citation Excerpt :
The increased inflammatory burden of the arterial wall may yield local extracellular acidification and increase in local temperature [13,14]. The acidic pH associated with thick, lipid-rich atherosclerotic lesions enhances the interaction of LDL with arterial wall proteoglycans [15–17]. This shows that the inflammatory process itself and the derived responses contribute to the progression of atherosclerosis.
A rigorous processing of adsorption data from quartz crystal microbalance technology was successfully combined with the data obtained by partial filling affinity capillary electrophoresis and molecular dynamics for the clarification of the temperature effect on the interaction of a major glycosaminoglycan chain chondroitin-6-sulfate (C6S) of proteoglycans with low-density lipoprotein (LDL) and with a peptide fragment of apolipoprotein B-100 (residues 3359–3377 of LDL, PPBS). Two experimental techniques and computational atomistic methods demonstrated a nonlinear pattern of the affinity of C6S at temperatures above 38.0 °C to both LDL and PPBS. The temperature affects the interaction of C6S with LDL and PPBS by influencing the structural behavior of glycosaminoglycan C6S and/or that of LDL.
First in vivo application of microwave radiometry in human carotids: A new noninvasive method for detection of local inflammatory activation
2012, Journal of the American College of Cardiology
Citation Excerpt :
The characteristics of these plaques include large lipid core, thin fibrous cap, increased infiltration of inflammatory cells, and neovascularization (5,27). Previous studies showed that inflammation within the atherosclerotic plaques is correlated with thermal heterogeneity (7,28,29). Despite the advancements of imaging methods, currently there is no method for the in vivo noninvasive measurement of carotid plaque temperature (10,12,30).
This study investigated whether temperature differences: 1) can be measured in vivo noninvasively by microwave radiometry (MR); and 2) are associated with ultrasound and histological findings.
Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues.
Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (ΔT) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed.
ΔT was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p < 0.01). Fatty plaques had higher ΔT compared with mixed and calcified (p < 0.01) plaques. Plaques with ulcerated surface had higher ΔT compared with plaques with irregular and regular surface (p < 0.01). Heterogeneous plaques had higher ΔT compared with homogenous (p < 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher ΔT compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p < 0.01).
MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation.
Current imaging modalities to visualize vulnerability within the atherosclerotic carotid plaque
2008, Journal of Vascular Surgery
There is increasing evidence that plaque vulnerability, rather than the degree of stenosis, is important in predicting the occurrence of subsequent cerebral ischemic events in patients with carotid artery stenosis. The many imaging modalities currently available have different properties with regard to the visualization of the extent of vulnerability in carotid plaque formation.
Original published studies were identified using the MEDLINE database (January 1966 to March 2008). Manual cross-referencing was also performed.
There is no single imaging modality that can produce definitive information about the state of vulnerability of an atherosclerotic plaque. Each has its own specific drawbacks, which may be the use of ionizing radiation or nephrotoxic contrast agents, an invasive character, low patient tolerability, or simply the paucity of information obtained on plaque vulnerability. Functional molecular imaging techniques such as positron emission tomography (PET), single photon emission-computed tomography (SPECT) and near infra-red spectroscopy (NIRS) do seem able accurately to visualize and even quantify features of plaque vulnerability and its pathophysiologic processes. Promising new techniques like near infra-red fluorescence imaging are being developed and may be beneficial in this field.
There is a promising role for functional molecular imaging modalities like PET, SPECT, or NIRS related to improvement of selection criteria for carotid intervention, especially when combined with CT or MRI to add further anatomical details to molecular information. Further information will be needed to define whether and where this functional molecular imaging will fit into a clinical strategy.
Determination of atherosclerotic plaque temperature in large arteries
2008, International Journal of Thermal Sciences
Atherosclerotic plaques with high probability of rupture can be characterized by the presence of a hot spot in the arterial wall, which forms due to accumulation of inflammatory cells in the plaque. This paper presents calculations of the arterial wall temperature distribution of arteries affected by plaque. This analysis characterizes the factors affecting plaque temperature, such as vessel geometry, plaque size, inflammatory cell density and distribution, and blood flow pattern. Three vessel types which present high occurrence of plaque are studied: a stenotic straight artery, an arterial bend and an arterial bifurcation corresponding to a human aorta, a coronary artery and a carotid bifurcation, respectively. The atherosclerotic plaque is located in the sites of low shear stress, and a local heat generation is introduced to account for the presence of inflamed plaque.
It is shown that the plaque temperature correlates positively to inflammatory cell density and layer thickness, whereas the plaque temperature varies inversely with the depth of the inflammatory cell layer or fibrous cap. From the calculations, it is observed that the best spot to measure plaque temperature is between the middle and the far edge of the plaque where maximum temperature is located. The results contribute to understanding the physical characteristics of the plaque structure and its relationships to plaque temperature, and also suggest a tool to understand the arterial wall temperature measurements obtained with novel catheters.

View all citing articles on Scopus

^☆: Supported in part by the US Army’s Disaster Relief and Emergency Medical Services (DREAMS) Grant No. DAMD 17-98-1-8002. Drs. Casscells, Willerson, Naghavi, and Madjid are shareholders in Volcano Therapeutics, Inc., a company developing diagnostic and therapeutic modalities for vulnerable plaque.

View full text

Thermal detection of vulnerable plaque☆

Abstract

Section snippets

Mechanism of heat production in atherosclerotic plaques

Ex vivo thermal detection studies

In vivo thermal detection: animal studies

In vivo thermal detection: human studies

Conclusion

Cardiol Clin

J Mol Cell Cardiol

J Am Coll Cardiol

Atherosclerosis—an inflammatory disease

N Engl J Med

Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture

Biochem J

Expression of the uncoupling protein UCP-2 in macrophages of unstable human atherosclerotic plaques

Circulation

Thermal detection of cellular infiltrates in living atherosclerotic plaquespossible implications for plaque rupture and thrombosis

Lancet

pH heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque

Atherosclerosis